Transcript Lecture9- Tolerance and ADR study notes 11-12.pptx

ilos
By the end of this lecture you will be able to :
Distinguish difference between tolerance
and desensitization ( tachyphylaxis ) and
reasons for their development
 Recognize patterns of adverse drug
reactions (ADR)
TOLERANCE, DESENSITIZATION &
ADVERSE DRUG REACTIONS
Phenomenon of variation in drug response, where by
there is a gradual diminution of the response to the
drug when given continuously or repeatedly
TOLERANCE and DESENSITIZATION
DIMINUTION OF A RESPONSE
Rapid, in the
course of few
minutes
Gradual in the
course of few
days to weeks
TACHYPHYLAXIS /
DESENSITIZATION
TOLERANCE
These SHOULD BE DISTINGUISHED
FROM
Loss of effectiveness of
antimicrobial agent
Resistance
REASONS FOR DEVELOPMENT OF TOLERANCE
PRE
RECEPTOR
EVENTS
EVENTS AT
RECEPTORS
↓ drug availability at the relevant
receptors due to pharmacokinetic variables
Drug becomes:
> metabolized or excreted
< absorbed
altered distribution to tissues
eg. Barbiturates  metabolism of
Contraceptive pills =  it
availability
POST
RECEPTOR
EVENTS
Nullification of drug
response by a
physiological adaptative
homeostatic response
Antihypertensive effects of ACE
Is become nullified by activation
of renin angiotensin system by
NSAIDs
LOSS OF THERAPEUTIC EFFICACY
Refractoriness
REASONS FOR DEVELOPMENT OF TOLERANCE
PRE
RECEPTOR
EVENTS
EXHUSTION
OF MEDIATORS
Depletion of mediator
stores by amphetamine
EVENTS AT
RECEPTORS
BINDING
ALTERATION
POST
RECEPTOR
EVENTS
DOWN
REGULATION
REASONS FOR DEVELOPMENT OF TOLERANCE
EVENTS AT
RECEPTORS
BINDING
ALTERATION
Phosphorylation of R
by ß-adrenoceptors
→ ↓ activation of AC
to related ionic channel
[functional defect]
DOWN REGULATION
BINDING ALTERATION
DOWN
REGULATION
↓ number of
receptors.
Isoprenaline
activation to b
receptors →↑ R
recycling by
endocytosis
[structural defect]
DOWN REGULATION
Harmful or seriously unpleasant effects occurring
at doses intended for therapeutic effects.
Type A
Type C
Type E
Augmented
Continuous
End-of-Use
PREDICTABLE
Occurs during chronic
drug administration
Occurs consequent but
in excess of drug primary
pharmacological effect.
Of quantitative nature
Occurs upon sudden
stoppage of chronic
drug use due to
existing adaptive
changes present
Type B
Type D
Bizzar
Delayed
UNPREDICTABLE
Occurs different [heterogenous / idiosyncrotic ] to
known drug pharmacological effect usuallydue to
patient’s genetic defect or immunological response.
Of qualitative nature
Occurs after long period
of time even after drug
stoppage
Type C
Continuous
e.g. Patients can develop
1. Osteoporosis secondary to chronic corticosteroid intake
2. DEPENDENCE:
a. Psychological [Craving] as by cannabis
b. Psychological [Craving] + Physical withdrawal manifestations (syndrome)
= ADDICTION as by morphine
Type D
Delayed
Long after patients can show:
-TERATOGENICITY after retinoids
- CARCINOGENICITY after smoking nicotine
Type E
End-of-Use
e.g. Patients on stoppage of
- Clonidine develop rebound hypertension
- Morphine develop withdrawal syndrome
Type A Augmentation
Pharmacological predictability
Nature
Dose dependent
Onset of symptoms
Type B Idiosyncrotic
Yes
No
Quantitative [ extension Qualitative [ immune or
of pharmacology effect ]
genetic base]
Yes (dose response
No (dose response
relationship present)
relationship absent)
Usually Rapid
Usually delayed
Incidence and morbidity
High
Low
Mortality
Low
High
Treatment
Dose adjustment or
Substitute by > selective
+ Antagonize unwanted
effect of 1st drug
Stop drug
+ Symptomatic
treatment
Example
Bradycardia b- ADR
Blockers
Hemorrhage Warfarin
Apnea succinylcholine
Thrombocytopenia
Quinine
HYPERSENSITIVITY REACTIONS
Drug or its bi-product react as antigens & provoke immune response
that results in damage to the tissue Hypersensitivity Reaction
IgE
1st
exposure
to a drug
IgG
Sensitization
T killer
cells
Repeated
exposures
HYPERSENSITIVITY REACTION
HYPERSENSITIVITY REACTION
TYPE I
Anaphylaxsis
Urticaria,
rhinitis,
bronchial
asthma
by Penicillin.
TYPE II
Cytotoxic
TYPE III
Immune complex
TYPE IV
Cell mediated
Haemolytic
Serum sickness (fever
Contact
arthritis enlarged lymph dermatitis by
anaemia
nodes, urticaria)
thrombocytopenia
local
by Sulphonamides
by Quinidine
anesthetics
creams
Quiz?
The gradual diminution of response to
the drug that occurs gradual in the
course of few days to weeks is
A) anaphylaxsis
B) tolerance
C) tachyphylaxsis
D) idiosyncrasy
Quiz?
Teratogenicity to retinoids is
considered
A) Type C adverse drug reaction
B) Type I hypersensitivity reaction
C) Type C adverse drug reaction
D) Type III hypersensitivity reaction
Quiz?
An example of drug induced
cytotoxicity is
A) bronchial asthma by penicillin
B) haemolytic anemia by quinidine
C) serum sickness by sulphonamides
D) contact dermatitis by local anaesthetic creams